CN116444442A - 2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2h)-基)-n-芳基乙酰胺衍生物及其制备方法与应用 - Google Patents
2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2h)-基)-n-芳基乙酰胺衍生物及其制备方法与应用 Download PDFInfo
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Abstract
本发明涉及化学结构式I所示的2‑(5‑氟‑2,4‑二氧代‑3,4‑二氢嘧啶‑1(2H)‑基)‑N‑芳基乙酰胺衍生物及其药学上可接受的盐，药物组合物以及其在制备抗肿瘤药物中的应用：
Description
技术领域
本发明涉及一类新化合物、其制备方法与应用，具体是2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-芳基乙酰胺衍生物、其制备方法及其作为抗肿瘤药物的应用。
背景技术
目前，恶性肿瘤的治疗方法主要以化学治疗（药物治疗）为主，放射治疗，生物治疗和免疫治疗等为辅，但现今尚未发现更有效的治疗手段。
5-氟尿嘧啶是抗代谢药物中的一种，它的机制是5-氟尿嘧啶和它的衍生物通过N1位与脱氧核苷酸结合，抑制胸腺嘧啶合成酶发挥作用，导致胸腺嘧啶脱氧核苷酸不能有效合成，进而干扰DNA复制与合成，因其化学结构与嘧啶碱相似，而这嘧啶碱是机体内细胞增殖所必需的代谢物质。
虽然5-氟尿嘧啶在临床上有着广泛的应用，但由于其细胞选择性低、毒副作用大并且治疗剂量和中毒剂量相近，这些缺点在临床中给病人带来了极大的痛苦。为了降低药物毒副作用等缺点，将5-氟尿嘧啶进行结构修饰，优化分子结构，降低其毒性，提高其作用选择性，改善药物的体内代谢动力学过程，增加药物的体内稳定性。
2003年，Dominguez等[Bioorganic & Medicinal Chemistry, 2003, 11(3):315–323]描述了一系列5-氟尿嘧啶的前体药物，其中化合物A1在4.5 μM时可诱导横纹肌肉瘤细胞形态和表型分化，可以作为选择性破坏未分化细胞的替代方法。
2007年，Tian等[Molecules, 2007, 12(11): 2450–2457]合成了6个5-氟尿嘧啶类似物，初步体外抗肿瘤活性研究表明对B16、K562和CHO细胞具有一定的细胞毒性，部分化合物能有效地抑制肿瘤细胞的生长，其中化合物 A2显示较高的抑制活性。
2019年，Liu等[MedChemComm, 2019, 10: 1370–1378]描述了一系列五环三萜-5-氟尿嘧啶结合物，并对其抗肿瘤活性进行了评价，结果显示化合物A3具有一定的抗增殖活性，对多药耐药细胞株A549/T和Bel-7402/FU的IC50值分别为20.73和19.77 μmol/L。
2020年，Mustafa等[Systematic Review Pharmacy, 2020, 11(3): 482–489]描述了(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)肉桂酸甲酯衍生物，体外抗癌活性测试发现，部分化合物对MCF-7、Hela、AMN3和SKG细胞的增殖具有一定的抑制作用，其中化合物A4的IC50值分别为290、327、298和325 μmol/L。
2021年，Salerno等[Journal of Enzyme Inhibition and MedicinalChemistry, 2021, 36(1): 1378–1386]合成了5-氟尿嘧啶和血红素氧合酶1抑制剂相互作用的化合物A5，初步细胞毒性评价表明化合物A5对人前列腺癌细胞(DU145)和肺癌细胞(A549)的IC50值分别为46.93和1.45 μmol/L。
发明内容
本发明解决的技术问题是提供一类2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-芳基乙酰胺衍生物、其制备方法、药物组合物和用途。
为解决本发明的技术问题，本发明提供如下技术方案：
本发明技术方案的第一方面是提供了一类如结构式Ⅰ所示2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-芳基乙酰胺衍生物及其药学上可接受的盐：
其中，R选自：2-甲氧基、3-甲氧基、4-甲氧基、2,3-二甲氧基、2,4-二甲氧基、2,5-二甲氧基、2,6-二甲氧基、3,4-二甲氧基、3,5-二甲氧基、2-羟基-3-甲氧基、2-羟基-4-甲氧基、2-羟基-5-甲氧基、2-羟基-6-甲氧基、3-羟基-2-甲氧基、3-羟基-4-甲氧基、3-羟基-5-甲氧基、3-羟基-6-甲氧基、4-羟基-2-甲氧基、4-羟基-3-甲氧基、4-羟基-3,5-二甲氧基、2-羟基-3-乙氧基、2-羟基-4-乙氧基、2-羟基-5-乙氧基、2-羟基-6-乙氧基、3-羟基-2-乙氧基、3-羟基-4-乙氧基、3-羟基-5-乙氧基、3-羟基-6-乙氧基、4-羟基-2-乙氧基、4-羟基-3-乙氧基、4-羟基-3,5-二乙氧基、2,3,4-三甲氧基或3,4,5-三甲氧基。
进一步的，优选的化合物选自：2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(2-甲氧基苯基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(3-甲氧基苯基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(4-甲氧基苯基)乙酰胺、N-(2,3-二甲氧基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(2,4-二甲氧基苯基)-2-(5-氟-2,4-二氧-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(2,5-二甲氧基苯基)-2-(5-氟-2,4-二氧-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(2,6-二甲氧基苯基)-2-(5-氟-2,4-二氧-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(3,4-二甲氧基苯基)-2-(5-氟-2,4-二氧-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(3,5-二甲氧基苯基)-2-(5-氟-2,4-二氧-3,4-二氢嘧啶-1(2H)-基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(2-羟基-3-甲氧基苯基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(2-羟基-4-甲氧基苯基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(2-羟基-5-甲氧基苯基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(2-羟基-6-甲氧基苯基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(3-羟基-2-甲氧基苯基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(3-羟基-4-甲氧基苯基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(3-羟基-5-甲氧基苯基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(3-羟基-6-甲氧基苯基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(4-羟基-2-甲氧基苯基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(4-羟基-3-甲氧基苯基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(4-羟基-3,5-二甲氧基苯基)乙酰胺、N-(3-乙氧基-2-羟基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(3-乙氧基-2-羟基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(4-乙氧基-2-羟基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(5-乙氧基-2-羟基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(6-乙氧基-2-羟基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(2-乙氧基-3-羟基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(4-乙氧基-3-羟基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(5-乙氧基-3-羟基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(6-乙氧基-3-羟基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(2-乙氧基-4-羟基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(3-乙氧基-4-羟基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(3,5-二乙氧基-4-羟基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(2,3,4-三甲氧基苯基)乙酰胺或2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(3,4,5-三甲氧基苯基)乙酰胺。
本发明技术方案的第二方面是提供了2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-芳基乙酰胺衍生物的制备方法，其特征在于它的制备反应如下：
其中，R选自：2-甲氧基、3-甲氧基、4-甲氧基、2,3-二甲氧基、2,4-二甲氧基、2,5-二甲氧基、2,6-二甲氧基、3,4-二甲氧基、3,5-二甲氧基、2-羟基-3-甲氧基、2-羟基-4-甲氧基、2-羟基-5-甲氧基、2-羟基-6-甲氧基、3-羟基-2-甲氧基、3-羟基-4-甲氧基、3-羟基-5-甲氧基、3-羟基-6-甲氧基、4-羟基-2-甲氧基、4-羟基-3-甲氧基、4-羟基-3,5-二甲氧基、2-羟基-3-乙氧基、2-羟基-4-乙氧基、2-羟基-5-乙氧基、2-羟基-6-乙氧基、3-羟基-2-乙氧基、3-羟基-4-乙氧基、3-羟基-5-乙氧基、3-羟基-6-乙氧基、4-羟基-2-乙氧基、4-羟基-3-乙氧基、4-羟基-3,5-二乙氧基、2,3,4-三甲氧基或3,4,5-三甲氧基。
本发明技术方案的第三方面是提供含有第一方面所述化合物及其药学上可接受的盐的药物组合物，该药物组合物含有治疗有效量的本发明的2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-芳基乙酰胺衍生物及其药学上可接受的盐，以及任选的含有药用载体。其中所述的药用载体指药学领域常用的药用载体；该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物及其药学上可接受的盐与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂组合，制成适于人或动物使用的任何剂型。本发明化合物及其药学上可接受的盐在其药物组合物中的含量通常为0.1%~95 %重量百分比。
本发明化合物及其药学上可接受的盐或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物及其药学上可接受的盐可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物及其药学上可接受的盐制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物及其药学上可接受的盐与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物及其药学上可接受的盐先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物及其药学上可接受的盐片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物及其药学上可接受的盐的胶囊剂。
为将本发明化合物及其药学上可接受的盐制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明技术方案的第四方面是提供本发明所述2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-芳基乙酰胺衍生物及其药学上可接受的盐以及第三方面所述药物组合物在制备抗肿瘤药物方面的应用。
有益技术效果：
本发明的2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-芳基乙酰胺衍生物是一类新型的具有抗肿瘤活性的化合物。
具体实施方式
以下实施例旨在说明本发明而不是对本发明的进一步限定。
实施例1
一种2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-芳基乙酰胺衍生物，其分子式如下式：
其中，R选自：2-甲氧基、3-甲氧基、4-甲氧基、2,3-二甲氧基、2,4-二甲氧基、2,5-二甲氧基、2,6-二甲氧基、3,4-二甲氧基、3,5-二甲氧基、2-羟基-3-甲氧基、2-羟基-4-甲氧基、2-羟基-5-甲氧基、2-羟基-6-甲氧基、3-羟基-2-甲氧基、3-羟基-4-甲氧基、3-羟基-5-甲氧基、3-羟基-6-甲氧基、4-羟基-2-甲氧基、4-羟基-3-甲氧基、4-羟基-3,5-二甲氧基、2-羟基-3-乙氧基、2-羟基-4-乙氧基、2-羟基-5-乙氧基、2-羟基-6-乙氧基、3-羟基-2-乙氧基、3-羟基-4-乙氧基、3-羟基-5-乙氧基、3-羟基-6-乙氧基、4-羟基-2-乙氧基、4-羟基-3-乙氧基、4-羟基-3,5-二乙氧基、2,3,4-三甲氧基或3,4,5-三甲氧基。
实施例2
2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酸的制备
62.5 mmol氢氧化钾溶于15 mL水溶液中，室温下搅拌使氢氧化钾溶解，随后加入15.4 mmol 5-氟尿嘧啶，继续搅拌使其溶解后，升温至80℃，缓慢滴加21.6 mmol溴乙酸，继续搅拌反应11 h，反应过程通过TLC监测。将反应液冷却至室温，用浓盐酸调节pH至2~3，减压旋转蒸发除去反应液中的水，粗产物用适量的乙醇重结晶，抽滤，干燥得2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酸，白色固体，m.p. >250℃，收率97%。
实施例3
2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(3-甲氧基苯基)乙酰胺(M1)的制备
1.0 mmol 2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酸、1.2 mmol 3-甲氧基苯胺、1.2 mmol HOBt、0.2 mmol DMAP和2.0 mmol EDCI溶于10 mL DMF中，室温下搅拌反应48 h，反应过程通过TLC监测。反应完成后，用饱和NaHCO3溶液淬灭，反应混合物用EtOAc稀释，用EtOAc (2×50 mL)提取。合并的有机提取物在无水Na2SO4上干燥，过滤，并在减压下旋转蒸发浓缩，通过硅胶柱色谱法提纯，干燥得2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(3-甲氧基苯基)乙酰胺(M1)，白色粉末，m.p. 220~221℃，收率91%。1HNMR (500 MHz, DMSO-d6) δ：11.88 (s, 1H, NH), 10.31 (s, 1H, CONH), 8.09 (d, J =6.8 Hz, 1H, C4HN2), 7.29 (s, 1H, C6H4), 7.22 (m, 1H, C6H4), 7.08 (d, J = 8.1Hz, 1H, C6H4), 6.65 (d, J = 8.1 Hz, 1H, C6H4), 4.49 (s, 2H, COCH2), 3.72 (s,3H, OCH3), 13C NMR (126 MHz, DMSO-d6) δ：165.38, 158.98, 157.64, 157.43,150.59, 139.70, 131.28, 129.16, 111.30, 109.12, 105.15, 54.97, 50.21。
实施例4
N-(3,4-二甲氧基苯基)-2-(5-氟-2,4-二氧-3,4-二氢嘧啶-1(2H)-基)乙酰胺(M2)的制备
1.0 mmol 2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酸、1.2 mmol 3,4-二甲氧基苯胺、1.2 mmol HOBt、0.2 mmol DMAP和2.0 mmol EDCI溶于10 mL DMF中，室温下搅拌反应48 h，反应过程通过TLC监测。反应完成后，用饱和NaHCO3溶液淬灭，反应混合物用EtOAc稀释，用EtOAc (2×50 mL)提取。合并的有机提取物在无水Na2SO4上干燥，过滤，并在减压下旋转蒸发浓缩，通过硅胶柱色谱法提纯，干燥得N-(3,4-二甲氧基苯基)-2-(5-氟-2,4-二氧-3,4-二氢嘧啶-1(2H)-基)乙酰胺(M2)，白色粉末，m.p. 245~246℃，收率92%。1HNMR (500 MHz, DMSO-d6) δ：11.80 (s, 1H, NH), 10.37 (s, 1H, CONH), 8.11 (d, J =6.7 Hz, 1H, C4HN2), 7.35 (s, 1H, C6H3), 7.06 (d, J = 8.7 Hz, 1H, C6H3), 6.89(d, J = 8.7 Hz, 1H, C6H3), 4.49 (s, 2H, COCH2), 3.71 (s, 3H, OCH3), 3.71 (s,3H, OCH3)；13C NMR (126 MHz, DMSO-d6) δ：164.86, 157.65, 157.45, 156.06, 150.19,144.93, 132.23, 130.47, 112.07, 110.52, 104.18, 55.69, 55.32, 50.11。
实施例5
2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(4-甲氧基苯基)乙酰胺(M3)的制备
1.0 mmol 2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酸、1.2 mmol 4-甲氧基苯胺、1.2 mmol HOBt、0.2 mmol DMAP和2.0 mmol EDCI溶于10 mL DMF中，室温下搅拌反应48 h，反应过程通过TLC监测。反应完成后，用饱和NaHCO3溶液淬灭，反应混合物用EtOAc稀释，用EtOAc(2×50 mL)提取。合并的有机提取物在无水Na2SO4上干燥，过滤，并在减压下旋转蒸发浓缩，通过硅胶柱色谱法提纯，干燥得2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(4-甲氧基苯基)乙酰胺(M3)，白色粉末，m.p. 237~238℃，收率89%。1H NMR(400 MHz, DMSO-d6) δ：11.89 (s, 1H, NH), 10.12 (s, 1H, CONH), 8.09 (d, J = 6.8Hz, 1H, C4HN2), 7.52~7.43 (m, 2H, C6H4), 6.93~6.85 (m, 2H, C6H4), 4.46 (s, 2H,COCH2), 3.72 (s, 3H, OCH3)。
实施例6
2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-芳基乙酰胺衍生物的抗肿瘤活性
1．抗肿瘤活性实验原理
活细胞的线粒体中的琥珀脱氢酶能使外源性的MTT还原为难溶性的蓝紫色结晶物甲臜(Formazan)并沉积在细胞中，而死细胞无此功能。二甲基亚砜能溶解细胞中的紫色结晶物，用酶联免疫检测仪在490 nm波长处测定其光吸收值，可间接反映细胞数量。在一定细胞数范围内，MTT结晶物形成的量与细胞数成正比。
2．抗肿瘤活性实验方法
细胞系：4T1（鼠源乳腺癌细胞）及TPC-1（人乳头瘤甲状腺癌细胞），南京大学现代工程与应用科学实验室赠予。
试剂：噻唑蓝(MTT)、含抗生素的RPMI 1640 培养液（南京凯基生物科技发展有限公司）、胎牛血清（浙江天杭生物科技有限公司）、胰酶（南京凯基生物科技发展有限公司）、96 孔培养板（无锡耐思生命科技股份有限公司）、二甲基亚砜[Sigma（上海）公司]。
仪器：1300 series A2型生物安全柜（美国 Thermo 公司）、CLM-170B-8-CN型CO2培养箱(ESCO)、BDS400型倒置显微镜（重庆奥特光学仪器有限责任公司）、Multiskan GO型酶标仪（美国 Thermo 公司）、超纯水制备仪（美国 Milli-Q 公司）。
实验操作：试样对于4T1（鼠源乳腺癌细胞）及TPC-1（人乳头瘤甲状腺癌细胞）的测试。一次实验过程中，每种试样设置7个浓度梯度(2500 ng/L、1250 ng/L、625 ng/L、312.5ng/L、156 ng/L、78 ng/L和39 ng/L)，DMSO溶解药物，孵育72小时，每个浓度四个平行试样，每组实验平行3次，并通过空白组对照得出结论。酶标仪检测各孔OD值，检测波长490 nm。
3．检测样品：化合物2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(3-甲氧基苯基)乙酰胺(M1)和N-(3,4-二甲氧基苯基)-2-(5-氟-2,4-二氧-3,4-二氢嘧啶-1(2H)-基)乙酰胺(M2)。
4．抗肿瘤活性评价
分别以4T1（小鼠乳腺癌细胞）、TPC-1（人乳头瘤状甲状腺癌细胞）细胞进行孵育，DMSO溶解药物，孵育72小时，用MTT法检测细胞活性，结果表明化合物2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(3-甲氧基苯基)乙酰胺(M1)和N-(3,4-二甲氧基苯基)-2-(5-氟-2,4-二氧-3,4-二氢嘧啶-1(2H)-基)乙酰胺(M2)对癌细胞的细胞毒性较大，化合物M1和M2对4T1（小鼠乳腺癌细胞）及TPC-1（人乳头瘤甲状腺癌细胞）的IC50值列入表1。
表1 2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-芳基乙酰胺衍生物对4T1和TPC-1细胞的IC50
活性测试结果显示，2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-芳基乙酰胺衍生物对乳腺癌4T1细胞和人乳头瘤状甲状腺癌TPC-1细胞具有良好的抑制活性，可用于制备抗肿瘤药物。
Claims (5)
1.一类化学结构式Ⅰ所示2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-芳基乙酰胺衍生物及其药学上可接受的盐：
其中，R选自：2-甲氧基、3-甲氧基、4-甲氧基、2,3-二甲氧基、2,4-二甲氧基、2,5-二甲氧基、2,6-二甲氧基、3,4-二甲氧基、3,5-二甲氧基、2-羟基-3-甲氧基、2-羟基-4-甲氧基、2-羟基-5-甲氧基、2-羟基-6-甲氧基、3-羟基-2-甲氧基、3-羟基-4-甲氧基、3-羟基-5-甲氧基、3-羟基-6-甲氧基、4-羟基-2-甲氧基、4-羟基-3-甲氧基、4-羟基-3,5-二甲氧基、2-羟基-3-乙氧基、2-羟基-4-乙氧基、2-羟基-5-乙氧基、2-羟基-6-乙氧基、3-羟基-2-乙氧基、3-羟基-4-乙氧基、3-羟基-5-乙氧基、3-羟基-6-乙氧基、4-羟基-2-乙氧基、4-羟基-3-乙氧基、4-羟基-3,5-二乙氧基、2,3,4-三甲氧基或3,4,5-三甲氧基。
2.一类2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-芳基乙酰胺衍生物及其药学上可接受的盐，选自下列化合物：
2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(2-甲氧基苯基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(3-甲氧基苯基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(4-甲氧基苯基)乙酰胺、N-(2,3-二甲氧基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(2,4-二甲氧基苯基)-2-(5-氟-2,4-二氧-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(2,5-二甲氧基苯基)-2-(5-氟-2,4-二氧-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(2,6-二甲氧基苯基)-2-(5-氟-2,4-二氧-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(3,4-二甲氧基苯基)-2-(5-氟-2,4-二氧-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(3,5-二甲氧基苯基)-2-(5-氟-2,4-二氧-3,4-二氢嘧啶-1(2H)-基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(2-羟基-3-甲氧基苯基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(2-羟基-4-甲氧基苯基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(2-羟基-5-甲氧基苯基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(2-羟基-6-甲氧基苯基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(3-羟基-2-甲氧基苯基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(3-羟基-4-甲氧基苯基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(3-羟基-5-甲氧基苯基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(3-羟基-6-甲氧基苯基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(4-羟基-2-甲氧基苯基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(4-羟基-3-甲氧基苯基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(4-羟基-3,5-二甲氧基苯基)乙酰胺、N-(3-乙氧基-2-羟基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(3-乙氧基-2-羟基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(4-乙氧基-2-羟基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(5-乙氧基-2-羟基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(6-乙氧基-2-羟基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(2-乙氧基-3-羟基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(4-乙氧基-3-羟基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(5-乙氧基-3-羟基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(6-乙氧基-3-羟基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(2-乙氧基-4-羟基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(3-乙氧基-4-羟基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、N-(3,5-二乙氧基-4-羟基苯基)-2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺、2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(2,3,4-三甲氧基苯基)乙酰胺或2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-(3,4,5-三甲氧基苯基)乙酰胺。
3.权利要求1所述的2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-芳基乙酰胺衍生物的制备方法，其特征在于，它的制备反应如下：
式中，R的定义如权利要求1所述。
4.权利要求1或2所述的2-(5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-N-芳基乙酰胺衍生物及其在药学上可接受的盐在制备抗肿瘤药物方面的应用。
5.一种药物组合物，包括权利要求1或2中至少一种化合物和制药学上可用的载体。
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